The present invention relates to novel benzopyrans having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of hypertension.
European Patent Publication 158,923 discloses classes of chromans that are described as having blood pressure lowering activity.
The present invention discloses compounds represented by formula (I) ##STR4## wherein R.sup.1 is trifluoromethoxy or .beta.,.beta.,.beta.-trifluoroethoxy; R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, lower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing 5 to 8 carbon atoms, ##STR5## or R.sup.2 and R.sup.3 are joined to form (--CH.sub.2 --).sub.n wherein n is 4 to 7; or R.sup.2 and R.sup.3 are joined together to form (--CH.sub.2 --).sub.m CO-- wherein m is 3 to 6; or R.sup.2 and R.sup.3 are joined together to form ##STR6## wherein R.sup.4 is selected from the group consisting of hydrogen, alkoxy containing 1 to 5 carbon atoms, amino or mono- or disubstituted alkyl amino wherein said alkyl groups contain 1 to 5 carbon atoms and the pharmaceutically acceptable salts and solvates thereof.
Preferred aspects of the present invention are compounds of formula (I) wherein R.sup.1 is trifluoromethoxy and R.sup.2 and R.sup.3 are joined to form ##STR7## and the pharmaceutically acceptable salts and solvates thereof.
The preferred compounds of the present invention are designated
2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-2,3-dihydro-1H-i soindol-1-one, PA0 2-[2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-4-yl]-1,2-dihydro-3H-p yrrolo[3,4-c]pyridin-3-one,
and the pharmaceutically acceptable salts thereof.
The present invention provides a process for the production of compounds of formula (I) which comprises the reaction of a compound of formula (II) ##STR8## wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above with NaH, CS.sub.2 and MeI to form the substituted intermediate xanthate compound of formula (III) ##STR9## wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above and heating said xanthate compound of formula (III) to produce the compound of formula (I).
Alternatively, compounds of formula (II) wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above are condensed with methanesulfonyl chloride in the presence of triethylamine to afford the intermediate methanesulfonate of the formula (IIIa) ##STR10## wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above. Said methanesulfonate (IIIa) is treated sequentially with sodium iodide (at room temperature) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at slightly elevated temperature to produce the compound of formula (I).
Some of the required compounds of formula (II) can be prepared by the reaction of a compound of formula (IV) ##STR11## where R.sub.1.sup.1 is R.sup.1 as defined hereinbefore or a group or atom convertible thereto, with a compound of formula (V) ##STR12## wherein X is chlorine, bromine, or iodine; R.sup.4 is as defined above; and p is 1 or 2 to produce the compound of formula (VIla). ##STR13## wherein R.sup.1,R.sup.4 and p are as defined above.
Some of the required compounds of formula (II) can be prepared by the reaction of a compound of formula (IV) ##STR14## wherein R.sub.1.sup.1 is R.sup.1 as defined hereinbefore or a group or atom convertible thereto, with a compound of formula (VIa) or (VIb) ##STR15## wherein R.sup.4 is as defined above to produce the compound of formula (VIIa), wherein p is 1 or (VIIb) ##STR16## wherein R.sup.1 is as defined above.
The present invention provides a process for the reaction of the compound (VIIa) with NaH, CS.sub.2 and MeI to form the substituted intermediate xanthate compound of formula (VIII) ##STR17## wherein R.sup.1 and R.sup.4 are as defined above. The intermediate xanthate (VIII), without isolation, is heated and directly converted to the desired product of formula (IX) ##STR18## wherein R.sup.1 and R.sup.4 are as defined above.
It is particularly preferred that the reaction between the compounds of formula (IV) and (V) is carried out under alkylation conditions so as to facilitate the formation of the desired bonds, for example, by heating in the presence of potassium carbonate.
The present invention also provides a process for the reaction of the compound (VIIb) with methanesulfonyl chloride in the presence of triethylamine to form the methanesulfonate of formula (X) ##STR19## wherein R.sup.1 is as defined above.
The intermediate methanesulfonate (X) is sequentially treated with sodium iodide at room temperature followed by 1,8-diazabicyclo[5.4.0]undec-7-ene at 70 to 90.degree. C. to produce the desired product of formula (XI) ##STR20## wherein R.sup.1 and R.sup.4 are as defined above.
Examples of conversions of a group or atom from R.sub.1.sup.1 into R.sup.1 are generally known in the art of synthetic chemistry. For example, if it is desired to obtain a compound of formula (I) wherein R.sup.1 is a trifluoroethoxy group it is possible to convert a compound of formula (I) wherein R.sup.1 is a hydroxy group or a protected hydroxy group to the desired trifluoroethoxy group by deprotecting the hydroxy group and alkylating the hydroxy group in a conventional manner. Examples of protecting agents and their addition and removal are generally known in the art.
The compounds of this invention are capable of forming acid addition salts with therapeutically acceptable acids. The acid addition salts are prepared by reacting the base form of the appropriate compound of formula (I) with one or more equivalents, preferably with an excess, of the appropriate acid in an organic solvent, for example, diethyl ether or an ethanol diethyl ether mixture.
These salts, when administered to a mammal, possess the same or improved pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the basic compounds. Suitable acids to form these salts include the common mineral acids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids, e.g. ascorbic, citric, lactic, aspartic or tartaric acid; and acids which are sparingly soluble in body fluids and which impart slow-release properties to their respective salts, e.g. pamoic or tannic acid or carboxymethyl cellulose. The preferred salt is the hydrochloride salt. The addition salts thus obtained are the functional equivalent of the parent base compound in respect to their therapeutic use. Hence, these addition salts are included within the scope of this invention and are limited only by the requirement that the acids employed in forming the salts be therapeutically acceptable.
The compounds of formulas (IV) and (V) are known compounds or can be prepared by conventional procedures from known compounds.
As mentioned previously, the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of hypertension. These compounds may also be useful in the treatment of asthma, irritable bladder syndrome, and imitable bowel syndrome.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier. In particular, the present invention provides an antihypertensive pharmaceutical composition which comprises an antihypertensive effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example in a manner similar to that used for known antihypertensive agents, diuretics and .beta.-blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of hypertension.
The present invention further provides a method of treating hypertension in mammals including man, which comprises administering to the afflicted mammal an antihypertensive effective amount of a compound or a pharmaceutical composition of the invention.
Synthetic Process A relates to the preparation of a compound of formula (I) ##STR21## wherein when R.sup.2 is hydrogen R.sup.3 is benzoyl, furoyl or R.sup.2 and R.sup.3 are joined to form isoquinolone or isoindolone ##STR22## wherein R.sup. is defined above; X is chlorine, bromine or iodine; R.sup.6 is benzoyl, furoyl, or ##STR23## wherein p is 1 or 2; R.sup.7 is lower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing 5 to 8 carbon atoms, or benzyl; R.sup.8 is benzoyl or furoyl; and R.sup.4 is as defined above.
The production of preferred compounds of the present invention is illustrated by Synthetic Process B and Synthetic Process C ##STR24##